integr med res 7 ( 2 0 1 8 ) 109–125

Available online at www.sciencedirect.com

Integrative Medicine Research

journal homepage: www.imr-journal.com

Review Article

Integration of botanicals in contemporary

medicine: road blocks, checkpoints and go-ahead
signals

Neha Arora Chugh, Shreya Bali, Ashwani Koul ∗

Department of Biophysics, Panjab University, Chandigarh, India

a r t i c l e i n f o a b s t r a c t

Article history: The use of botanicals for maintaining good health and preventing diseases is undisputed.
Received 22 September 2017 The claimed health benefits of natural health products and herbal medicines are based on
Revised 7 March 2018 traditional claims, positive results obtained in preclinical studies and early phase clinical
Accepted 22 March 2018 trials that are not backed by safety and efficacy evidences approved by regulatory agen-
cies. Although, the popularity of botanicals is growing, health care practitioners of modern
medicine seldom recommend their use because of ill equipped database of their safety and
Keywords: potency. This review discusses problems that preclude botanicals from integrating into the
Botanicals mainstream contemporary therapeutics and cues that provide impetus for their realisation.
Complementary and alternative © 2018 Korea Institute of Oriental Medicine. Publishing services by Elsevier B.V. This is an
medicine open access article under the CC BY-NC-ND license
Contemporary medicine (http://creativecommons.org/licenses/by-nc-nd/4.0/).

origin and around 27 anticancer drugs including actinomycin

1. Introduction
D, paclitaxel, vincristine, topotecan, dexamethasone, etopo-
side, tamoxifen etc. developed during the period 1940–2010,
The use of plants for therapeutic purposes can be traced
were from natural sources.8–10
back to the Neanderthal period and since then their use
The search for medicinally relevant compounds from natu-
for remedial purposes has been growing.1 Animals have
ral sources is relatively easy because they have a history of use
also been consuming plants for their healing properties
in prevention and/or treatment of diseases. Thus, drug discov-
and such serendipitous occurrences have provided leads for
ery from herbal sources is experience driven and on the con-
identifying plants with medicinal potentials.2–5 Many of the
trary, the search of a clinically useful compound ‘de novo’ with
drugs in modern therapeutics are natural products or have
no source leads is a ‘shot in the dark’. Drug development from
been derived from them (plants, microbes, marine organ-
plants is carried out in three elaborate steps namely: pre-drug
isms/plants, insects, animals).6–9 Data collected over the years
stage; quasi drug stage and full drug stage.11 Pre-drug stage
from drug manufacturing community has indicated that about
50% of drugs available in the last several decades had natural

∗
Corresponding author. Department of Biophysics, Panjab University, South Campus, Sector 25, Chandigarh-160014, India.
E-mail addresses: drashwanikoul@yahoo.co.in, ashwanik@pu.ac.in (A. Koul).
https://doi.org/10.1016/j.imr.2018.03.005
2213-4220/© 2018 Korea Institute of Oriental Medicine. Publishing services by Elsevier B.V. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
110
is the first stage of drug development and involves the infor-
mation driven selection of herbs or plants, based on results
obtained in animal studies, experience obtained by their
indigenous use and through self-medication. Thus, fruits, veg-
etables, spices, and traditional medicinal plants are obvious
targets for this approach. Once cleared through the pre-drug
stage, the plant enters the quasi drug stage which involves
the preparation of extracts, screening of phytochemicals,
structure and composition elucidation, bioactivity evaluation
and identification of possible lead compounds using mod-
ern techniques.12 Once the lead compound is identified, it is
structurally modified if needed. It is then evaluated in animal
models, in-vitro studies and clinical trials and upon approval;
it enters as a marketed drug. All these comprise the full drug
stage. Although, modern, scientific and high through put tech-
nologies are available for the drug discovery process, however,
unless these take care of the ADMET profile (i.e., absorption,
distribution, metabolism, excretion, and toxicity) they may not
be able to successfully produce a good medicinal product.
The drug development process is growing at an enor-
mous pace and it is undeniable that chemically synthesized
drugs have revolutionised the field of medicine. Despite, the
well established system of modern conventional medicine,
plants still continue to provide benefits for medicinal purposes
to about 80% of the world population, largely in develop-
ing countries.13,14 Over 70–95% of the population in Africa,
Asia, Latin America and Middle East use some form of tra-
ditional medicine as their first line of treatment.15 Majority of
the hospitals in China have well established units rendering
treatment through traditional healing systems.16,17 In China,
traditional Chinese medicine (TCM) was very widely used for
controlling severe acute respiratory distress syndrome and in
Africa, traditional herbal medicine was used to alleviate symp-
toms associated with human immune deficiency virus (HIV)
infection.18,19 Plant based remedies are the primary form of
healthcare amongst the unprivileged sections of populations
because of poverty and limited access to modern medicine.
Complementary and alternative medicine (CAM) therapies
is divided into two broad categories namely drug based CAM
therapies and non-drug based CAM therapies.20 Plants con-
stitute about 80% of the drug based CAM therapies. There
has been a change of perception among the general pub-
lic and adoption of alternative remedies has increased even
in the developed nations.13,21 Particularly, herbal medicine
is drawing attention and has given a boost to the phy-
topharmaceutical market in international trade. Global giants
in pharmaceutical manufacturing have been aggressively
investing in herbal medicine.17,19 Chinese herbal medicine
registered an increase of 20 percent in sales in 2012 from
the previous year; reaching to about US$83 billion.22 The
international market for herbal supplements and remedies
is expected to reach US$115 billion by 2020, with Europe
being the largest and Asia-Pacific being the fastest growing
market.23 Worldwide, about 35 000 plant species are being
used for medicinal purposes.24 The Indian herbal industry
uses about 960 plant species and among these about 178
have huge consumption surpassing hundred metric tonnes.25
Among the European countries, Germany and France have the
largest sales of herbal medicines.17 The use of herbal supple-
ments is also very popular in United States of America (USA)
Integr Med Res ( 2 0 1 8 ) 109–125
and their eminence for purported health benefits is on a con-
tinuous rise.26
Modern medicine targets the disease usually by employing
a single agent (monotherapy). Traditional healing systems like
ayurveda employ different approaches like medicinal herbs,
yoga, dietary control, meditation, prayers etc for restoring
balance in the body and alleviation of diseases. Traditional
systems of medicine are based on the holistic treatment of
the patient which also takes into consideration behavioral,
physiological, psychological effects of drugs on the mind-body
complex. Ayurvedic medicinal preparations contain combi-
nation of medicinal plants, minerals, metals etc. Polyherbal
formulations are recommended as they provide synergism of
positive effects and antagonism of negative effects and drug
associated side effects.27,28 The use of multiple herbs in com-
bination with other ingredients and modalities serves well to
provide symptomatic relief alongside targeting the disease at
the tissue level. The modern chemotherapeutic approaches
which are largely ‘molecule driven’ have taken an edge over
traditional healing systems because plant based preparations
and other complementary modalities are slow to act and
provide relief gradually, in comparison to the drugs used in
modern medicine.28,29 However, the ill effects emanating from
the use of these drugs has provided grounds for renewed inter-
est in traditional therapies.30,31
The increase in adoption of herbal remedies may be
ascribed to: a general preference of natural therapies and
aversion for other interventions like surgery, allopathic
medicines etc; inclination towards self-medication based
upon experience; affordable cost of herbal medicines and
ease of availability; side effects associated with conventional
medicines (especially in cases of chronic problems) and grow-
ing promotion of herbal medicines.13,32 Herbal remedies are
generally used and/or recommended for maintaining good
health, alleviation of chronic problems and rarely for acute
and/or life-threatening problems.33,34 People begin using alter-
native forms of treatment, including herbal medicine when
conventional medicine is ineffective or for pain palliation in
case of long standing problems like cancer, arthritis etc.17 The
use of natural dietary supplements among the general popu-
lation is also very popular in an attempt to prevent cancer.35,36
The use of dietary supplements (containing natural products)
among cancer patients in USA has become very popular and
many patients begin using new dietary supplements with
natural ingredients after being given a cancer diagnosis.37
Botanicals when sold commercially are often referred to as
‘natural health products (NHPs) or herbal medicinal products
(HMPs)’. They are available as single isolated/enriched com-
pounds or as complex mixtures of several biologically active
compounds and they may be obtained from single herb or
combination of herbs (polyherb formulations). They are pre-
pared in a variety of ways and can be taken in the form
of decoction, tinctures, essential oils, teas, syrup, ointments,
salves, and tablets/capsules that contain powered form of the
whole plant/plant part or dried extract.17
Although, the adoption of herbal medicine/botanicals in
preventing and/or curing diseases through self-medication
instigated by promotion in popular media has seen a surge,38
however, its acceptance among health care practitioners is not
very encouraging.39–41 Strange as it may appear, but many
N.A. Chugh et al
professional health practitioners admitted to having little
knowledge regarding herb supplements, which discourages
their prospective clinical trials and use. It was revealed in a
survey that oncologists did not have enough knowledge about
the use of herbs and dietary supplements and did not receive
any training in this regard. Due to lack of concrete evidence
and scientifically robust studies evaluating their potential
risks and benefits, oncologists find it challenging to give advice
to patients regarding their use, probable positive or negative
impact along with the use of other treatment modalities like
radiotherapy, chemotherapy, hormonal therapy, immunother-
apy etc.37,42
Although, many botanicals are in the pipeline of clini-
cal trials however, they have met with little success because
of the study limitations.43 Therefore, health care practition-
ers seldom recommend/prescribe their use in ailments. The
widespread promotion of the natural products/dietary sup-
plements claiming their health benefits through television,
internet etc is one of the major sources through which the con-
sumers gain knowledge about these products. These claims
are usually not backed by any regulatory authority and gen-
erally are based on positive results obtained in pre-clinical
investigations in animal models, cell lines and/or small early
phase clinical trials. The use of these products bereft of any
safety and efficacy studies is likely to have some detrimental
effects. For instance, in USA, for cancer, several clinical trials
have been conceived and initiated but Food and Drug Admin-
istration (FDA) has not approved any phytoproduct in cancer
therapy. A lot of natural dietary supplements have undergone
phase 2 trials; however, majority failed to enter the follow up
phase 3 trials.37,43 Plant extracts encounter steep failure rates
in clinical trials which is in sharp contrast to the enormous
benefits they exhibit in pre-clinical studies.37 Thus, they fail to
obtain the regulatory approval as potential treatment options.
This review discusses various problems encountered with
botanicals/phytomedicine and its possible integration with
the contemporary medicine (Fig. 1). Some of the impediments
are inherent to this healing system and there are other prob-
lems which fall in the ambit of regulations and procedures.
Even though, there has been a paradigm shift in the mindset of
people regarding the use of natural products, however unless
backed by their safety and efficacy proofs they are unlikely to
be recommended as popularly as the contemporary form of
medicine.
2. Problems that keep botanicals away from
being included in the mainstream alternatives
for health promotion and disease management
Scientifically sound and robust procedures and guidelines
have been laid down for assessing safety, efficacy, pharma-
cokinetics, quality, good manufacturing practices (GMP), post
marketing surveillance etc of conventional putative drugs.
However, such rigorous procedures are lacking for herbal
products. In addition, clinical trials with herbal products are
associated with poor design and reporting. This is surprising
considering the fact that this form of medicine enjoys such
tremendous popularity amongst the people of both developed
111
and developing nations and of all cultures and religion. All
these reasons account for the hazy reputation of botanicals.
2.1. Challenges of clinical trials: impediments in trial
designing, poor design of trials and their reporting,
economically unviable trials
Carrying out of randomised, placebo-controlled trials is essen-
tial in the evaluation of any drug for health benefits or disease
mitigation.37 Usually herbal medicines have a peculiar color,
taste and smell which make it difficult to carry out placebo-
controlled trials.44,45 In addition, the decision to choose an
‘active reference medicine/comparator’ as a herbal product
or one that from modern medicine is an area of concern.
Quite literally, it is very difficult and impractical to have active
and control groups with similar organoleptic features when
using herbal products.46 The differences in the type of for-
mulations used, although containing the same ingredients
yield different results owing to the varying bioavailability of
the active constituents.47 Although, the inclusion and exclu-
sion criteria for enrolling patients in clinical trials with HMPs
could be based either on modern or traditional practice, how-
ever, confounding situations could arise if the disease criteria
vary in both the systems.46 The inclusion and exclusion cri-
teria for trials with herbal medicine are challenged by the
non-uniformity in medical systems across countries.48 Over-
looking such issues can allow for faulty interpretations and
conclusions. For instance, the criteria for patient selection by
American researchers for testing the potential of a herb on
heart failure would be based on the disease features recog-
nised by the New York Heart Association, which drastically
differs from the ‘ying and yang’ perspective of disease devel-
opment by the practitioners of TCM.19
Ayurveda (Indian form of traditional herbal medicine)
treats patients on the basis of ‘prakriti’ or the ‘psycho-
somatic’ constitution. This is an individualistic thing and
ayurveda recommends compounding/mixing of herbs, dosage
and duration for an individual. Therefore, the effect of one par-
ticular treatment regimen of an ayurvedic remedy would be
inappropriate to generalise to a subject population with vary-
ing psychosomatic constitution in clinical studies.49,50 Such
generalisation could also be difficult to apply to other tra-
ditional forms of medicine like TCM which lays stress on
personalised medicine.51
Clinical evaluation of herbal drugs has been found to have
shortcomings in trial design, improper execution and weak
data analysis.52 Inappropriate number of patients in trials,
improper randomisation and selection bias has been observed
in previous clinical trials with herbal medicines.53,54 Enrolling
fewer participants in the trial make it difficult to reach to
a statistically significant conclusion. Many a times, doubts
and objections have been raised on the methodology and
inferences drawn from clinical trials of herbal treatments.
In addition, reports on herbal drugs are incomplete with
respect to the recommendations of Consolidated Standards
of Reporting Trials (CONSORT) guidelines,55–57 explaining the
elusiveness and contradiction in their safety and efficacy
reviews.58–60 Considering these limitations, Cochrane reviews
had concluded that with herbal drugs no well-designed trial
has been conducted and that there is not enough supporting
112
Fig. 1 – Inclusion of botanicals in contemporary medicine: obstacles encountered and potential solutions (a brief summary)
evidence for their safety and effectiveness for the proposed
clinical condition.61–67 Poor quality of trials and their reporting
give way to under or overestimation of the treatment effects
which are bound to have undesired effects. Also, the conclu-
sions made regarding the efficacy are surrounded by doubts
linked to poor quality of reporting and poor design and con-
duct of trials.68 Very few clinical trials involving traditional
herbal medicines in Africa and China have been reported to be
of adequate quality and problems have been recognised with
regard to number of patients recruited, placebo preparation
etc.69–71
Integr Med Res ( 2 0 1 8 ) 109–125
Repetitive and large scale clinical trials are complicated,
time consuming and expensive procedures. Usually, the com-
pound/drug molecule undergoing clinical trials is patented
by the pharmaceutical company and these are then sold at
a premium providing opportunities for the manufacturers to
gain profits. Usually, manufactures of food products, herbal
products etc are not given patent protection and therefore
face price competition. Limited profits incurred dissuade them
from paying the hefty costs involved in large phase 3 trials.37
In USA, since FDA approval is not mandatory for selling
dietary supplements containing herbal ingredients, therefore,
N.A. Chugh et al
manufactures avoid going through randomised, placebo-
controlled phase 3 trials and continue promoting their prod-
ucts based upon the positive results obtained in phase 2 trials.
Due to the fact that plants cannot be patented, therefore drug
manufacturers see fewer opportunities for huge profit making.
In USA, approximately $5.5 billion to 5.9 billion and 15years is
the amount of money and time spent in bringing a new drug to
the market.72,73 Without huge profits in sight, very few com-
panies are willing to invest in satisfying FDA requirements.
2.2. Problems of complexity: difficult pharmacokinetic
evaluation and dosage calculation
Pharmacokinetic studies are difficult to carry out on poly-
chemical natural products.74 This is because many a times,
the active ingredient/active principle is not known, and also
the presence of several different active components make
the pharmacokinetic evaluation difficult and complex.75–77
The problems of pharmacokinetic profiling in phase I of drug
development are further compounded in cases when poly-
herbal formulations are used. This requires standardisation
of several active compounds and their estimation in the body
fluids.78 Pharmacokinetic evaluation becomes very elaborate
when patients simultaneously seek treatment from tradi-
tional and contemporary medicine systems.
Pharmacokinetic herb–drug interactions are mediated by
modulations in cytochrome P450s (CYPs) and drug trans-
porters (P-glycoprotein).79 CYPs are primarily involved in drug
metabolism and are abundantly present in liver and small
intestine. CYP3A4, one of the isoform of CYPs is an impor-
tant drug metabolising enzyme (DMEs) that is involved in the
herb–drug interactions.80 It is responsible for oxidising about
60% of drugs to less active or readily excretable metabolites
and its level of activity determines the bioavailability of the
drug. Any alteration in the activity of CYP3A4 gets reflected in
the bioavailability of drugs that are oxidised by this CYP. For
instance, it has been observed that grapefruit reduces enteric
CYP3A4 activity, thereby elevating the levels of some drugs to
toxic levels.81 On the contrary, St.John’s wort, which is used in
the treatment of depression increases CYP3A4 activity and P-
glycoprotein, consequentially leading to diminished clinical
response of drugs like cyclosporine and indinivir.82,83 Since,
the drug entities of both the systems are metabolised by the
same monooxygenase system (DMEs) in the body, therefore
pharmacokinetic interactions are inevitable. Further, poly-
morphism in DMEs is likely to have its own influence on the
way individuals respond to herbal medicines.84
Conventional medicines are carefully studied for their dose
effect response and accordingly safest dose is calculated tak-
ing into consideration body weight, drug interactions etc and
possibly minimising the scope for negative effects.44,85,86 Dose
calculation is a tricky area to resolve in herbal medicine due
to several reasons. Very often the active ingredient/s and the
quantity is unknown in the herb and its raw material by which
the herbal medicine is prepared. More so, very rarely it is
known as to how the levels of the active constituents vary
with the kind of processing the herb undergoes for preparation
of drug.87 In vitro and pre-clinical studies involve prolonged
exposure to high concentrations of the phytoproduct. This
may be difficult to imitate in humans because of limited oral
113
bioavailability, known and unknown adverse effects and drug
interactions rendering such treatment regimens unsuitable.88
Because of the inadequate studies determining the interac-
tions of herbal medicines with the conventional medicines
there is a likelihood of adverse drug reactions (ADRs). Not only
this, insufficient information is available regarding the dose
dependent effects and possible side effects of the same on
consumption of higher doses. For instance, although herbal
remedies are effective in controlling progression of liver dis-
eases, however some of the compounds present in these
medicines can have deleterious effects. Thus, this necessitates
careful dose escalation and efficacy testing which involves
complex pharmacokinetic and dose calculation studies.89 Tra-
ditional forms of medicine used in China, Japan, Korea, India
etc are mainly used in the form of decoction which involves
boiling of the plant parts to extract/enrich the compounds
of interest. Decoctions suffer from disadvantages like dosage
quantification, composition stability, quality control etc. Dis-
crepancies in the reported dosage and treatment duration
of herbal remedies; poor standardisation and lack of qual-
ity control of herbal preparations, presence of several active
compounds are some issues that make the dose calculation
tedious.77
2.3. Product categorization affects safety assessments:
pre-marketing and post-marketing safety checks
Herbal products are classified and regulated depending
upon countries/jurisdiction.90 The regulatory requirements
for products labelled as ‘food’ are less stringent than those
labelled as ‘drugs’ or ‘medicinal products’. This categorisa-
tion varies between countries and sometimes even within
the countries.91,92 Product categorisation can be a difficult
task, sometimes vague, presenting challenges to the regu-
latory authorities. The claims made regarding the products
enlists them either into food or drugs i.e. products which claim
no health or medicinal benefits (treat or prevent diseases) are
labelled as ‘food’. For instance, if products containing garlic
are claimed to exhibit health benefits then they are regulated
as drugs, else are sold as food.68
In USA, herbal products are classified as dietary supple-
ments or special foods and since they are not considered
as drugs, therefore they can be sold without clinical trials
and do not require pharmacovigilance reporting.93 Thus, FDA
does not subject them to the same strict and thorough inten-
sity checks of proof and safety. They are regulated under the
Dietary Supplement Health and Education Act, which allows
their use without having them to clear the strict quality con-
trol tests of Drugs and Cosmetics Acts (1994). FDA only reviews
these products and does not approve them. Accordingly, it is
not mandatory for manufacturers to test them in clinical trials
before marketing them, thus allowing for any untoward effects
that could occur with their use. FDA can disallow a com-
pany from making a supplement after it has been shown to
cause adverse effects.94 Several such cases have been reported
where herbal products have been recalled after they were
found containing banned substances or substances unfit for
consumption like prescription drugs etc. FDA banned the sale
of ephedra following reports of ephedra-related toxicity and
deaths.95 This is in striking contrast to the regulations for
114
prescription and non-prescription drugs which are required
to be proven safe before selling. Pharmacovigilance report-
ing (ADR reporting) is also not mandatory for manufacturers
of herbal dietary supplements.96 In the European Union (EU),
herbal products are classified either as herbal medicines or as
food supplements depending upon the claims made. Herbal
medicines in EU are required to satisfy safety and quality
standards but food supplements are not required to do so.
Complexity arises in cases when the same herb or mixture
of herbs is being supplied as herbal medicine and dietary sup-
plement. Thus, labelling a herbal product as drug or food has
implications in its pre-marketing (quality control, clinical tri-
als) and post marketing safety checks (pharmacovigilance).96
In China, natural products are considered as medicinal prod-
ucts and therefore are subjected to similar level of regulatory
control as for the conventional medicines. The regulatory
guidelines for countries like Canada, Singapore, Australia
etc vary and regulate the products accordingly.68 This non-
uniformity in product categorisation not only affects their
pre-market and post-market control, their safety and efficacy,
but also poses challenges in trans-national movement of prod-
ucts.
2.4. Challenges of pharmacovigilance: complexity of
nomenclature and consumer related issues
Since herbal drugs available worldwide come from China,
India, Brazil, Africa, several countries of Europe, South Amer-
ica etc, therefore there are problems that come up due to
diversity. This brings to the forefront questions such as what
should be the appropriate naming system (Latin, pharmaceu-
tical, generic, herbal drug name) and accurate validation of
the constituent herbs. Plants/herbs are generally known via
their Latin scientific name, vernacular name, pharmaceutical
name or pharmacopoeial name or specific herbal drug names
(as used in TCM or Indian herbal medicine). Sometimes, differ-
ent herbal ingredients are known by a single name allowing
for misidentification and inadvertent use of herbal products
leading to undesired effects.68 The roots of Aristolochia fangchi,
Stephania tetrandra and Cocculus trilobus are commonly known
as Fang ji. A. fangchi (Guang Fang Ji) was mistakenly consumed
instead of S. tetrandra (Han Fang Ji) for its weight loss benefits
and consumers reported severe renal problems. Upon careful
analysis it was found that inadvertent consumption of aris-
tolochic acid containing A. fangchi (Guang Fang Ji) products
was responsible for such adverse effects.97–99 This was fol-
lowed by a ban of aristolochic acid containing herbal products
in EU, USA and Australia. However, misidentification of herbs
due to confusion/similarity in common names continued the
production and consumption of aristolochic acid containing
herbal products.100–104 Product labelling of drugs may use one
or more of these naming systems and at times the drugs are
even sold without any labels. The non-uniformity in describ-
ing herbal constituents makes ADR and analysis confounding,
sometimes wrongly implicating a herb to the observed neg-
ative outcomes. Although, common names are frequently
used in USA and EU for the purpose of reference, however,
EU regulatory authorities recommend the use of Latin scien-
tific names.96 Reporting of herbal ADRs is of use only if the
reporter is aware of what herb/product was used. This requires
Integr Med Res ( 2 0 1 8 ) 109–125
correct identification of the plant/herb by the user. Inade-
quate or inappropriate use of names can cause confusion. For
instance, ADRs reporting by referring to the use of ‘ginseng’
could point out to a variety of plants, their species or even
unrelated plants. ‘Ginseng’ may refer to Panax ginseng C.A. Mey
or Panax quinquefolious (Burk.) F.H. Chen or other plants that
are also referred to as ginseng such as Eleutherococcus sentico-
sus (Rupr. & Maxim) Maxim (Siberian ginseng) or the unrelated
Withania somnifera (L.) Dunal (Indian Ginseng).96
It is a general perception among consumers that herbal
products have low risk so much so that anything natural is
synonymous with being safe. Any untoward effects observed
upon their consumption are generally not accepted and thus
‘cause–effect’ is not acknowledged in this case. Because of this
unawareness or paucity of information, users very often defer
the notion that their adoption of herbal remedy may be caus-
ing the observed unfavourable effects. Thus, their prolonged
use of herbal products could aggravate the problem. This is
particularly prevalent in the developing countries where use
of traditional herbal medicine is very popular and the system
of reporting ADRs is not well constituted. Surveys conducted
in developed nations like USA, Canada, United Kingdom
(UK), Australia have indicated that in these nations ‘passive
surveillance’ (voluntary spontaneous reporting) is the prime
source of gathering information about adverse effects ema-
nating from the use of medicinal products including NHPs.105
Although, passive surveillance has the advantage of reveal-
ing adverse effects in ‘real’ situations (large population/wide
consumer base) however, it has its limitations which can be
understood from the fact that since this system depends upon
voluntary reporting by the practitioners and/or patients, less
than 1% of adverse effects are reported.106 More so, patients
and health care practitioners are less likely to report adverse
effects associated with the use of NHPs than with the conven-
tional over the counter medications. It has also been observed
that physicians do not routinely inquire patients about use
of NHPs.106–111 Collectively; all these factors contribute to the
inadequacy of the passive surveillance to identify NHP associ-
ated harms. Active surveillance which involves keeping track
of adverse events using a carefully chalked out pre-organized
process are well established for conventional prescription
medicines but its application to NHPs is limited till date.112–114
For reasons known and unknown, patients do not divulge to
their clinicians about their use of herbal medicines.38 The
consumers are unaware of the importance of reporting the
use of herbal products or the adverse effects that may have
emanated from their use.115 In case of ill effects, patients and
health care professionals can report such events, but such
reporting is not mandatory.94 This leads to underreporting of
their adverse effects which contributes to their poor database
of toxicity and drug interactions.
2.5. Adverse reactions: an outcome of poor quality control,
herb–drug/herb–herb interactions
Several reports are available regarding the undesirable effects
of natural products, sometimes with very dire consequences.
Such observations have been reported amongst the users of
both developed and developing nations. The adverse effects
emanating from the use of herbal products can be attributed
N.A. Chugh et al
to the toxic effects of the inherent constituents or the adul-
terants/contaminants that are present in the preparation and
also herb–drug/herb–herb interactions. Owing to the poor
quality control standards and improper regulation of purity
and potency, herbal products fall short in comparison to
the conventional drugs. Poor quality control systems and
lack of stringent monitoring systems lead to the contamina-
tion/adulterations of herbal preparations.
Herbs obtained from polluted sites (areas with soil, water
or air pollution due industrial emissions) or poor farming
practices lead to the production of low quality products unfit
for human consumption.116,117 Herbal preparations although
prepared from same herbs each time may vary from batch
to batch because the phytochemical content could fluctuate
depending upon the harvesting time of the plant, climatic
conditions, geographical locations, harvesting methods and
environmental conditions could affect the presence of certain
elements (like heavy metals) depending upon the conditions
of water, soil and air in that region.32,86,118 Inappropriate stor-
age conditions can affect the quality of herbal products if they
get subjected to fungal or bacterial contamination and also
excessive drying can lead to loss of thermo-labile bioactive
constituents.84,86 Variations may also arise in preparations
such as extracts, decoctions etc between batches and amongst
manufacturers because of the variation in solvents, tempera-
ture, extraction time etc.17 The variability in the preparation
of the herbal products has implications in the health benefits
observed.67,86 The likely presence of allergens, pollens, toxins
(aflatoxin, mycotoxins brevetoxin B, yessotoxins, pecteno-
toxins, digoxin, sikimitoxin),119–122 microbes (Escherichia coli,
Salmonella, Listeria monocytogenes) and heavy toxic metals (mer-
cury, cadmium, lead, arsenic)123–128 could be contributing
to the observed adverse effects. Several cases of deliberate
addition of prescription drugs/other pharmaceutical products
(aminopyrine, phenylbutazone, phenacetin, dexamethasone,
indometacin, diazepam, hydrocortisone, fluocinolone ace-
tonide, diclofenac, mefenamic acid, clobetasol propionate,
phenytoin, methylsalicylate, prednisolone, indomethacin and
glibenclamide etc)123,124,129 in herbal products have come to
light. Cadmium, arsenic and lead have been detected in the
herbal products with levels exceeding the maximum permissi-
ble limits allowed by World Health Organisation (WHO).130,131
Inadvertent adulteration and substitution of herbal drugs with
incorrect plants/herbs due to confusion in vernacular names,
similarity in color and morphology etc is one of the reasons for
herbal products exhibiting undesired effects and being unfit
for consumption.132,133
Botanicals contain many pharmacologically active com-
pounds that exhibit biological effects in synergism or
antagonism. The presence of multiple compounds increases
the likelihood of interactions and it is considered that
herb–drug interactions could be more pronounced than
drug–drug interactions. These interactions could either serve
to enhance or diminish the pharmacological or toxicolog-
ical effects. Such interactions are mediated due to the
pharmacokinetic interference of one xenobiotic on another
xenobiotic, including metabolism, elimination, absorption etc.
All these events would modulate the dose response observed
and therapeutic or toxic effects.128 Although, interactions
could be positive, negative or neutral134 ; however, they could
115
be of concern if they act to cause damage. Many a times, there
is mislabelling/incomplete information provided on the labels
which increases the chances of herb–drug/herb–herb interac-
tions etc.135–137
Consumption of poor quality and adulterated products
has led to many un zfavourable effects ranging from mild
to moderate to severe; such as allergic reactions, respira-
tory complaints, pain, nausea, fatigue, gastrointestinal upset,
mood disturbances, muscle weakness, vomiting, confusion,
lethargy, seizures, sensory disturbances, compression frac-
tures, leucopoenia, convulsions, persistent hypoglycaemia,
Cushing’s syndrome, burns, dermatitis, meningitis, multi-
organ failure, arsenic, lead or mercury poisoning, malig-
nancies, hepatic and renal toxicity, cerebral edema, coma,
intracerebral haemorrhage, and even death.13,129,138
2.6. Discouraging reimbursement options
Worldwide, the use of CAM is increasing and has been a major
contributor to non-reimbursed medical or health expenditure.
Insurance companies refuse to cover CAM because they do
not completely believe the claims made by the proponents
of CAM.139 The decision makers in the insurance sector rea-
son out that in the current scenario of escalating healthcare
costs, and the constant emergence of new medical technolo-
gies and drugs has made them wary of expanding the health
care coverage options. They are of the opinion that coverage
should only be provided for health facilities that are backed
by a robust body of evidence for their safety and effective-
ness. Moreover, the lack of information on the use, cost and
overall cost-effectiveness of CAM makes it difficult for the
insurance companies to respond to the consumer needs and
hinders their ability to plan and execute policies related to
CAM reimbursement.139 In USA, the private insurance compa-
nies provide cover to varying degrees for the medical expenses
incurred from the accepted standard of care modalities and
reimbursement is usually not available for CAM and there-
fore must be paid of pocket by the consumers.140 Although,
CAM is very popularly used in UK, however it is not cov-
ered by the healthcare system.141 Since, the introduction of
Statutory Health Insurance Modernization Act in 2004, the
sale of herbal medicines has dropped in Germany because of
the exclusion of phytotherapeutics from reimbursement.142 In
USA, Medicare and Medicaid plans selectively provide cover
for chiropractic care, massage and acupuncture and have
excluded other forms of CAM including phytomedicine from
the reimbursement plans.143–145 Private insurance companies
have begun to include some forms of CAM however pre-
authorization, network restrictions, deductibles, co-payments
may be more than those laid out for conventional treatment
options. Additionally, the number of visits to the clinic/centre
and the extent of reimbursement may vary and be limited. In
EU, the reimbursement systems and policies differ between
the countries and in many countries, CAM is not included in
the national health supervision system.146 This implies that
patients seeking CAM treatment outside of their home country
may not be able to receive reimbursement because the CAM
reimbursement policies may differ between their country of
affiliation and the country of treatment.
116 Integr Med Res ( 2 0 1 8 ) 109–125

Table 1 – Medicinal effects exhibited by some plants

Plant Beneficial effects observed Reported literature
Azadirachta indica (Neem) Anti-cancer, anti-toxic, anti-viral 148–154,156,175
Lycopersicum esculentum (Tomato) Anticancer, anti-toxic 155,157
Aloe barbadensis (Aloe vera) Radioprotective 158,159
Withania somnifera (Ashwagandha) Anti-cancer, anti-toxic 160,161–164
Ginkgo biloba (Ginkgo) Neuroprotective, nootropic 165–168
Alpinia galangal (Greater galangal) Fertility 121,171
Punica granatum (Pomegranate) Fertility 121,171
Viscum album (Mistletoe) Immunity booster in cancer patients, mitigates 172
chemotherapy associated side effects
Thymus vulgaris (Thyme) Cold, cough, bronchitis, respiratory tract ailments 173
Pimpinella anisum (Aniseed) Cold, cough, bronchitis, respiratory tract ailments 173
Althea officinalis (Marshmallow) Cold, cough, bronchitis, respiratory tract ailments 173
Serenoa repens (Saw palmetto) Urinary tract ailments 174
Artemisia annua (Sweet wormwood) Anti-arthritis, anti-inflammatory 176

toxicity in rats.160 Several researchers have investigated the

3. Growing prospects of botanicals
Although there are numerous deterrents in the field of phy-
tomedicine, however, efforts are being concerted globally to
gain maximum benefits from the healing powers of plants.
Despite the apprehended hiccups, researchers worldwide
have been carrying out pre-clinical studies and clinical tri-
als with botanicals. Agencies like National Institute of Health
(clinicaltrials.gov), USA; European Medicines Agency [EMA]
(clinicaltrialsregister.eu), London; Indian Council of Medi-
cal Research (ctri.nic.in), India; National Health and Medical
Research Council, Australia (anzctr.org.au) etc in assistance
with several government and private institutes undertake
clinical trials and maintain their database. Typical pharma-
copoeial standards are difficult to apply to herbal medicines
and thus require broader and flexible approach in addressing
the problem of standardization.85,147 Systems and procedures
are being developed and revised to improve quality control,
safety and efficacy testing and pharmacovigilance.
3.1. Gathering scientific evidence for their proof of
function: pre-clinical and clinical studies
Plants are being continually explored for their medicinal prop-
erties in various animal, in-vitro models of diseases and
their suitability is also assessed in clinical studies (Table 1).
The underlying mechanisms behind the observed beneficial
effects are also being studied extensively. Several studies from
our laboratory and those of others have demonstrated the
anticancer effects of Azadirachta indica (Neem) extract against
cancer of various sites in mice.148–154 Lycopene enriched
tomato extract has proved beneficial against liver cancer in
mice.155 The anticancer activity has been ascribed to their
ability to modulate key signalling pathways like cell prolifer-
ation, apoptosis, carcinogen biotransformation, DNA repair,
immunomodulation etc. Neem and tomato extracts have
been effective in ameliorating doxorubicin induced cardiac156
and renal157 toxicity in mice. Administration of Aloe vera
extract provided protection against radiation induced testicu-
lar damage in mice by its ability to scavenge free radicals and
strengthen the cellular anti-oxidant defense system.158,159
Withania somnifera has the ability to mitigate arsenic induced
anticancer effects of Withania somnifera against skin, prostate,
colon, leukemia etc in animal models and cell lines.161–164
Extracts of Ginko biloba has neuroprotective effects as revealed
by its ability to prevent ischemic brain damage in mice165 and
trimethyltin neuronal toxicity.166 Ginko biloba has also exhib-
ited nootropic effects.167,168 Myriad number of phytochemicals
present in fruits, vegetables, herbs etc have been demon-
strated to have a wide range of biological activities that are
responsible for their medicinal properties.169,170
In a randomised control, double blinded trial, plant extracts
of Alpinia galanga (greater galangal) and Punica granatum
(pomegranate) were assessed for their effects in improving
semen quality in males (NCT01357044; clinicaltrials.gov) and
the study findings suggested that subfertile men can gain
an improved amount of motile ejaculated sperms by taking
tablets containing preparations of pomegranate fruit extract
and rhizome of greater galangal.121,171 A gel prepared with
Solanum undatum plant extract is being tested for its safety
and efficacy in patients of actinic keratosis (NCT01516515;
NCT02559934), vulvar pre-cancerous lesions and cutaneous
condyloma (NCT01676792). Mistletoe plant extract has been
assessed for its ability to improve immune function in stage
IV lung cancer patients receiving conventional chemother-
apy (NCT00079794). Its use as a complementary treatment
led to chemotherapy dose reductions, fewer hospitalisations
and reduction in non-haematological side-effects.172 Plant
extracts have been tested for their ability to provide relief
against nasopharyngitis and upper respiratory tract infec-
tion (EudraCT Number: 2005-005207-4). A combined herbal
preparation of dry ivy leaf extract, decoction of thyme and
aniseed, and mucilage of marshmallow root was tested for
its efficacy and tolerability in open clinical trial and this
preparation alleviated cough in consequence of common
cold, bronchitis or respiratory tract diseases with formation
of mucus.173 Extract of Serenoa repens was analysed versus
placebo in the treatment of lower urinary tract symptoms
associated with benign prostatic hyperplasia (EudraCT Num-
ber: 2014-000222-38) and it was found effective in mitigating
inflammatory biomarkers in these patients.174 Polyherbal for-
mulations of neem and other plants in the form of cream
or tablet have been tested for their anti-human papilloma
virus (HPV) potential in women infected with HPV type 16.175
N.A. Chugh et al
Neem leaf extract in herbal mouth rinse has been assessed
for its effectiveness in controlling radiation induced mucositis
in oral cancer patients (CTRI.2014/11/005163; NCT01898091).
A randomised placebo-controlled clinical trial revealed alle-
viation of symptoms associated with osteoarthritis of the
hip and knee with the use of an extract of Artemisia annua
(ACTRN12614000259640).176 Although, these studies have met
with mixed results, however, positive results obtained in these
trials certainly pave a way ahead for plant based medicine to
be incorporated with conventional medicine.
4. Surmounting the challenges faced by
botanicals
4.1. Improving procedures and guidelines
Although, not strictly followed by all countries, protocols
for safety and toxicity testing have been devised by several
agencies including Union of Pure and Applied Chemistry,177
European Medicines Agency (EMA),178 and the European Food
Safety Authority.179 Considering the complexity of herbal
medicines viz a viz their content and action, organisations like
WHO, European Agency for the Evaluation of Medicinal Prod-
ucts and European Scientific Cooperation of Phytomedicine,
US Agency for Health Care Policy and Research, European
Pharmacopoeia Commission, Department of Ayurveda, Yoga,
Unani, Siddha, Homeopathy (India) are revising procedures
and developing new protocols to standardise phytotherapy.
Attempts are being made to resolve issues that occur due to
nomenclature problems. Kew’s Medicinal Plant Names Ser-
vices has developed a freely accessible global resource that
provides information about plant and plant products rel-
evant to policy making and health regulation, traditional
medicine, functional foods and pharmacological research.
This database provides information of medicinally relevant
plants pertaining to their frequently used vernacular, trade
and pharmaceutical names.180 The Uppsala Monitoring Cen-
tre (UMC) in collaboration with the Royal Botanic Gardens
has established an effective system for standardisation and
cross-referencing of herbal names in order to enable interna-
tional reporting of ADRs due to herbal drugs. UMC has also
been involved in developing the WHO herbal dictionary which
serves as an international reference source of herbal prod-
ucts. This dictionary allows identification of herbal products,
their bioactive constituents, possible therapeutic uses, coding
and analysis of drug safety data during pre and post market-
ing. Herbal monographs have been published by American
Herbal Pharmacopoeia, WHO, United States Pharmacopoeia,
European Pharmacopoeia, EMA, Indian Pharmacopoeia etc.
Emphasis is being laid to improve the quality of ADR report-
ing and specialised centres have been set up worldwide for
assistance in herbal pharmacovigilance. In USA, since herbal
products are sold as dietary supplements and not as drugs
therefore they are spared from pharmacovigilance obliga-
tions. However, health care practitioners and consumers are
being made aware of the benefits of ADR reporting and are
being guided to report ADR events to the FDA MedWatch
Scheme. In UK, Medicines and Healthcare Products Regula-
tory Agency has a system for reporting of ADRs. In the EU,
117
when any herbal product is classified as a medicine then
the manufacturers have pharmacovigilance obligations listed
under European directives and other national regulations.
This includes informing the regulatory agencies of any unto-
ward or unexpected effects.96 In UK, the Chinese Medicine
Advisory Service with the help of Royal Botanic Gardens Kew
helps with the enquiries on adverse effects and the identifi-
cation of the Chinese medicinal herb suspected to be causing
the effect. In Hong Kong toxicology centres in hospitals take
up multidisciplinary investigations related to herbal toxicity.
WHO Collaborating Centre for monitoring drug safety (UMC)
collects ADR reports from over 100 countries and collates
them with the purpose of addressing nomenclature issues
and possibly co-relating the ADR with the correct herb.181 The
database maintained by the UMC also provides useful infor-
mation on the pharmacokinetic and pharmacodynamic drug
interactions.182 Regulatory agencies around the world have
started making efforts to facilitate the harmonization of reg-
ulatory requirements.68 The Association of Southeast Asian
Nations (ASEAN) consists of ten member countries each with
its varying backgrounds of traditional medicine. ASEAN has
formed a harmonized regulatory framework for traditional
and HMPs. This framework includes common agreements
on additives, excipients, pesticide residue levels, labelling
requirements etc.183,184
4.2. Improving trial design and ensuring quality control
High quality scientific research intended for the safety and
efficacy of HMPs is essential to instil confidence in practition-
ers of conventional medicine to adopt HMPs as alternatives for
disease management. However, the high costs of research and
development deter the manufacturers of herbal products from
delving into this space. This deterrent can be surmounted
by applying for a patent. Although, it is difficult to claim
exclusive rights for growing herbs, spices, plants etc, however,
this should not dissuade the manufactures from venturing
into HMP research since patents can also be granted on the
basis of novelty related to processing and formulating HMP,
unique compositions and their intended use for a medical
purpose.185–188 Patents have been granted for HMP based on
novel poly herb compositions, dosage forms, establishment
of new processes for isolation and standardization of active
compounds.186
Clinical trials carried out with placebos and/or reference
medicines before marketing are very important in revealing
potential adverse effects emanating from the use of a partic-
ular drug. However, these clinical trials are of a short duration
and are incapable of providing information on problems (such
as long term effects) that are not comprehensively addressed
by clinical trial protocols. Therefore, to evaluate long term
toxicity and safety potentials, long-term carcinogenicity tests,
reproductive and teratogenicity potentials should be assessed.
Moreover, many a times some rare and severe adverse effects
resulting due to interactions with drugs and nutrients come
to the forefront in subgroups of people not included in the
randomized control trials (RCTs). Such events are likely to be
detected only when the drug is in use by a larger section of the
population. Post-marketing surveillance of HMPs could help in
keeping track of such effects.52
118
The researchers should resort to high quality clinical
trials and adhere to good reporting. Considering the short-
falls in trial reporting, the CONSORT statement has been
amended with an aim to improve research and report-
ing quality with botanicals. Recommendations have been
made with context to complete and transparent reporting
of trials.57,189,190 Due emphasis has been laid on the stan-
dardization of the HMP because many a times the amount
of the active ingredient is not known and is known to vary
between preparations.60,191,192 The researchers must fully
describe the preparation of placebos used in HMP trials
so as to enable other researchers in carrying out related
placebo-controlled trials in order to control bias that may
occur due to the peculiar organoleptic properties of clinical
preparations and their respective placebos.193 Caution must
be practiced while designing clinical trials, laying stress on
the internal and external validity of the tests used thereof.
It is essential that the output of the results in the con-
trol conditions of the study find relevance in being used
outside the experimental settings of the study (refers to
the harmony between internal and external validity). This
implies that the study findings give meaningful insights
when applied in the ‘real’ situations.194,195 Further, for the
results to be externally valid it must be ensured that the
disease criteria for inclusion and exclusion should be rele-
vant with the diagnostic procedures currently used.48 Cluster
RCTs may be designed in order to establish the variabili-
ties of the practitioners while evaluating the efficacy of the
HMPs.48
It is known that ayurveda recommends personalized treat-
ment on the basis of an individual’s ‘prakriti’ and ‘tridoshas’.
‘Ayurgenomics’ is an upcoming field of study which serves to
bridge the gaps between genomic influences and Ayurvedic
principles. It is an integration of principles of genomics with
that of ayurveda and is aimed at studying inter-individual
differences to disease development and therapeutics by inter-
relating their psychosomatic constitution and their genetic
makeup.196,197 Such integration of disciplines could help in
designing trials with ayurvedic remedies.
As defined by the EMA, chemical markers are chemically
defined constituents or group of constituents intended for
the control of quality. Chemical markers are employed in the
standardization process to ensure that all batches contain a
defined amount of the active ingredient. The choice of the
chemical marker/s is essential to the quality of the herbal
product. These could be of two types: active markers and ana-
lytical markers. Active markers possess therapeutic potentials
while the latter ones are solely used for analytical purposes
and have no therapeutic value.198 It must be understood
that using a single active marker may not give a true repre-
sentation of the synergistic effects of the various bioactive
constituents present in the HMP.199,200 And similarly, using
an inappropriate analytical marker may not appropriately
give the indication of the potency or quality of HMP. Using a
non-specific analytical marker (e.g. quercetin, oleanolic acid
etc) will fail to recognize an adulterated HMP because of the
widespread presence of the marker being used.201,202 Using
a chemical marker alone for standardization and quality
control of HMP has its disadvantages. Therefore, other
methods must be used in tandem.
Integr Med Res ( 2 0 1 8 ) 109–125
Chromatographic fingerprinting is an analytical method
that employs high performance liquid chromatography,
thin layer chromatography (TLC), and gas chromatogra-
phy techniques.193,199,203 These techniques give a fingerprint
which is unique to a HMP. This fingerprint comprises of a
set of peaks which are characteristic of the herbal ingredi-
ents present. Thus, a unique fingerprint generated helps in
qualitative and quantitative analysis. Principal component
analysis can be used to compare fingerprint patterns to detect
adulteration.203,204 For polyherbal preparations204,205 and
preparations with closely related species (e.g. Heracleum spho-
ndylium and Heracleum sibiricum),206 a single chromatographic
analysis may be insufficient. To resolve the details of poly-
herbal formulations 2D-TLC,206,207 multiple chromatographic
fingerprinting143,154,193,204 and metabolite fingerprinting are
advisable.205,208–210
The regulators should perform targeted chemical analysis
on every batch of HMPs to check for adulterants. To evade
detection, manufacturers have started adding chemical drugs
or their modified analogues to the capsule shells.211–213 In
order to detect adulteration of this sort, reference spectra
of these shells and analogues should be recorded with the
aid of analytical techniques like liquid chromatography–mass
spectrometry (LC–MS),214,215 nuclear magnetic resonance
spectroscopy,215,216 infra-red spectroscopy.216 Considering the
transnational movement of HMPs, it is required that the reg-
ulators and manufacturers involve in information sharing
relating to detection of adulterants. Consumers can play their
part by buying HMPs from reputable and trust worthy sources.
In order to grapple with the unethical manufacturers and mis-
creants the consumers should be particular about details such
as manufacturing and expiry dates, batch numbers, names
and addresses of HMP manufactures. Having clear product
categorization will enable sufficient safety checks. It is known
that regulated HMPs are equipped with better product infor-
mation details enabling the customers to make more informed
choices, thus promoting the safe use of HMPs. With the grow-
ing popularity of HMPs and its worldwide acceptance, it is
required that authorities harmonize their regulatory require-
ments so as to bring about transparency and convenience for
manufacturers and consumers.
For the standardization of herbal drugs, tests can be
applied based on several established standards includ-
ing pharmacopeial standards, marker based phytochemical
assays, process control standards, storage standards, poly-
herbal reference standards, chemi-informatics approaches
based structural standards217 which include a range of phys-
ical, chemical and biological tests. Correct identification of
plant involves ascertaining the correctness of the plant cho-
sen based on its taxonomical classification, its morphological
features etc. The part of plant to be used should be confirmed
by matching its characteristic botanical features. Also, assess-
ing the level of exposure of the plant part to the environment
helps in deciding the levels of adulterants/contaminants.218
Removal of foreign organic matter involves removing other
organic matter (like weeds etc) that may sometimes come
along with the raw plant material. This is essential to avoid
interference during the standardization. Estimation of ash
values (total ash, sulphated ash, water soluble ash, acid insol-
uble ash) should be done by performing thermo-gravimetric
N.A. Chugh et al
analysis, differential thermal analysis and differential scan-
ning calorimetry.219–221 Moisture content must be determined
precisely to assess the actual weight of the drug. Low mois-
ture content increases the stability of the drug.217 Extractive
values which are indicative of the extractable chemical con-
stituents of the crude drug (under different solvent conditions)
must be evaluated as they are important in dose calculation.
The qualitative analysis of the crude drug involves screen-
ing of the various phytochemical constituents like flavonoids,
alkaloids, phenolics, carbohydrates etc which are of pharma-
cological significance.222 LC–MS has previously been employed
to standardize an aqueous extract of the mixture of twenty
herbs. This method provided twenty chemical compounds
to be used as reference markers.223,224 Quantitative analysis
should be performed for the levels of different elements, min-
erals, heavy metals etc. Microbial assays should be carried out
to establish the presence of mycotoxins, harmful fungi, bac-
teria and other microorganisms. Toxicology studies should be
performed in relevant animal models to generate LD50 values
and other relevant parameters which are required for subse-
quent studies by the drug regulators. These give information
about potentially toxic elements, pesticide levels etc.203,225
In order to ensure process control standards, batch analy-
sis should be done by performing intermediate testing using
appropriate methods. Tests should be performed to check
for any process induced toxicity and impurity. Storage stan-
dards should also be applied by determining storage standard
markers for raw material, stable intermediates from fractions,
processed material, and finished product. The shelf life of
the finished product in various conditions of temperature,
humidity should be also determined. Packaging material and
labeling standards should also be checked.217 Polyherbal ref-
erence standards are established by comparing the reference
standard of a single constituent in exclusion and its pro-
file in polyherbal formulations. Chemi-informatic approaches
include activity descriptors and its correlation modeling with
poly-constituent profile based indicators.
For the safe and effective use of quality botanicals, it
is utmost necessary that strict pre-market and post-market
evaluation is carried out. The dealers of the herbal products
(manufacturers, packagers, distributors, sellers etc) should be
made to satisfy specific legal requirements such as GMP, ADR
etc associated with the use of their HMPs. It is beyond doubt
that quality of starting material affects HMP quality. Therefore,
good agricultural practices (GAP) should be followed along
with GMP. In many countries, the manufacturers have to con-
form to GMP before a license can be granted for production of
HMP, although GAP is not legally mandatory for cultivators and
manufacturers.68 To ensure good quality of HMPs compliance
to both GMP and GAP should be made mandatory. Medicinal
plant cultivation through contract farming would ensure the
quality of the produce and minimise the variability in plant
preparations and maintain good quality products.
Through well designed educational and awareness pro-
grammes people need to be informed about the possible
good and adverse effects of NHPs. Health care practition-
ers/clinicians also need to be provided in depth knowledge
about medicinal plants/herbs and their putative health
effects. A better interaction between the clinicians and
patients with efficient exchange of information would help
119
reinstate the efforts that are being put to establish the
database of plant based medicine.
5. Conclusion
The growing popularity of over-the counter available health
products, dietary supplements, nutraceuticals obtained from
plants has highlighted certain issues which need to be
addressed at priority. These polychemical mixtures containing
many pharmacologically active compounds need a thorough
scientific and clinical evaluation in order to bring them to
mainstream therapeutics. The perception of natural being
safe can only be realised if these products are manufactured
under strict regulatory controls and assessed for their efficacy.
Through implementation of good agricultural, manufactur-
ing and supply practices it would be possible to improve the
quality of herbal medicines making them of a reproducible
quality. A collaborative effort of the researchers, clinicians and
patients is required to successfully establish herbal medicine
in health promotion and disease management. Although
evidences exist for the beneficial effects of plants against
diseases and in health promotion, however the use of plant
derived preparations can only be realised after the affirma-
tion of their safety and efficacy. With such reassurances it
could be possible to replace some synthetic drugs with herbal
medicines or use them in combination with other drugs; thus
enabling their integration into contemporary medicine.
Conflict of interest
Authors declare no conflicts of interest.
References
1. Winslow LC, Kroll DJ. Herbs as medicines. Arch Intern Med
1998;158:2192–9.
2. Fowler A, Koutsioni Y, Sommer V. Leaf-swallowing in
Nigerian chimpanzees: evidence for assumed
self-medication. Primates 2007;48:73–6.
3. Krief S, Jamart A, Mahe S, Leendertz FH, Mätz-Rensing K,
Crespeau F, et al. Clinical and pathologic manifestation of
oesophagostomosis in African great apes: does
self-medication in wild apes influence disease progression.
J Med Primatol 2008;37:188–95.
4. Raman R, Kandula S. Zoopharmacognosy: self medication
in wild animals. Resonance 2008:245–53.
5. Barden J, Weaver DF. The rise of micropharma. Drug Discov
Today 2010;15:84–7.
6. Maridass M, John de Britto A. Origins of plant derived
medicines. Ethnobotanical Leaflets 2008;12:373–87.
7. Gordaliza M. Terpenyl-purines from the sea. Marine Drugs
2009:833–49.
8. Newman DJ, Cragg GM. Natural products as sources of new
drugs from 1981 to 2014. J Nat Prod 2014;79:629–61.
9. Newman DJ, Cragg GM. Natural products as sources of new
drugs over the 30 years from 1981 to 2010. J Nat Prod
2012;75:311–35.
10. Ovadje P, Roma A, Steckle M, Nicoletti L, Arnason JT,
Pandey S. Advances in the research and development of
natural health products as main stream cancer
120
therapeutics. Evid Based Complement Alternat Med 2015;2015.
Article ID 751348, 12 p.
11. Pan SY, Zhou SF, Gao SH, Yu ZL, Zhang SF, Tang MK, et al.
New perspectives on how to discover drugs from herbal
medicines: CAM’s outstanding contribution to modern
therapeutics. Evid Based Complement Alternat Med 2013;2013,
25 p.
12. Sasidharan S, Chen Y, Saravanan D, Sundram KM, Yoga
Latha L. Extraction, isolation and characterization of
bioactive compounds from plants’ extracts. AJTCAM
2011;8:1–10.
13. Ekor M. The growing use of herbal medicines: issues
relating to adverse reactions and challenges in monitoring
safety. Front Pharmacol 2013;4:1–10.
14. Gopal NM, Tejaswini J, Mantry S, Kumar SA. International
standards of medicinal plants. IJIPSR 2014;2:2498–532.
15. Robinson MM, Zhang X. The world medicines situation 2011.
WHO; 2011.
16. World Health Organization (WHO). National policy on
traditional medicine and regulation of herbal medicines. Geneva:
World Health Organization (WHO); 2005. Report of WHO
global survey.
17. Benzie IFF, Wachtel-Galor S. Herbal medicine: biomolecular
and clinical aspects. 2nd ed. Boca Raton (FL): CRC
Press/Taylor & Francis; 2011.
18. De Smet P. Herbal medicine in Europe: relaxing regulatory
standards. N Engl J Med 2005;352:1176–8.
19. Tilburt JC, Kaptchuk TJ. Herbal medicine research and
global health: an ethical analysis. Bull World Health Organ
2008;86:577–656.
20. Pan SY, Gao SH, Zhou SF, Tang MK, Yu ZL, Ko KM. New
perspectives on complementary and alternative medicine:
an overview and alternative therapy. Altern Ther Health Med
2012;18:20–36.
21. Weeks LC, Strudsholm T. A scoping review of research on
complementary and alternative medicine (CAM) and the
mass media: looking back, moving forward. BMC
Complement Altern Med 2008;8:43.
22. WHO traditional medicine strategy 2014–2023. WHO; 2013.
23. Rinaldi A, Shetty P. Review: The facts, figures and challenges of
mixing modern and traditional medicine; 2015. Available from:
http://www.scidev.net/global/medicine/feature/traditional-
medicine-modern-times-facts-figures.html.
24. Yirga G, Teferi M, Kasaye M. Survey of medicinal plants
used to treat human ailments in Hawzen district, Northern
Ethiopia. Int J Biodivers Conserv 2011;3:709–14.
25. Sahoo N, Manchikanti P, Dey S. Herbal drugs: standards and
regulation. Fitoterapia 2010;81:462–71.
26. Rettner R. Herb supplements are the most common
complementary medicine in US; 2014. Available from:
http://www.livescience.com/44866-herb-supplements-
complementary-medicine.html.
27. Arora N, Koul A. A ‘complex solution’ to a ‘complex
problem’: tackling the complexity of cancer with
botanicals. Eur J Cancer Prev 2014;23:568–78.
28. Kumar S, Dobos GJ, Rampp T. The significance of Ayurvedic
medicinal plants. J Evid Based Complement Alternat Med
2016:1–8.
29. Chopra A, Saluja M, Tillu G. Ayurveda–modern medicine
interface: a critical appraisal of studies of Ayurvedic
medicines to treat osteoarthritis and rheumatoid arthritis.
J Ayurveda Integr Med 2010;1:190–8.
30. Garodia P, Ichikawa H, Malani N, Sethi G, Aggarwal BB.
From ancient medicine to modern medicine: ayurvedic
concepts of health and their role in inflammation and
cancer. J Soc Integr Oncol 2007;5.
31. Bhandaria M, Ravipati AS, Reddy N, Koyyalamudi SR.
Traditional ayurvedic medicines: pathway to develop
Integr Med Res ( 2 0 1 8 ) 109–125
anti-cancer drugs. J Mol Pharm Org Process Res
2015;3(3):1000130,
http://dx.doi.org/10.4172/2329-9053.1000130.
32. Bandaranayake WM. Quality control, screening, toxicity and
regulation of herbal drugs. Modern phytomedicine: Turning
medicinal plants into drugs. Weinheim:
Wiley-VCHGmbH&Co.KGaA; 2006:25–57.
33. Vickers A, Zollman C, Lee R. ABC of complementary
medicine: herbal medicine. BMJ 1999;319:1050–3.
34. Zollman C, Vickers A, Richardson J, editors. ABC of
complementary medicine. 2nd ed. Wiley Blackwell; 2008.
35. Patterson RE, Neuhouser ML, Hedderson MM, Schwartz SM,
Standish LJ, Bowen DJ. Changes in diet, physical activity,
and supplement use among adults diagnosed with cancer. J
Am Diet Assoc 2003;103:323–8.
36. Globe Newswire. 2015. Available from: http://
globenewswire.com/news-release/2015/04/23/727513/
10130416/en/Dietary-Supplements-Marketis-Expected-to-
Reach-US-179-8-Billion-Globally-in-2020-Persistence-
Market-Research.html.
37. Paller CJ, Denmeade SR, Carducci MA. Challenges of
conducting clinical trials of natural products to combat
cancer. Clin Adv Hematol Oncol 2016;14:447–55.
38. Tachjian A, Maria V, Jahangir A. Use of herbal products and
potential interactions in patients with cardiovascular
diseases. J Am Coll Cardiol 2010;55:515–25.
39. Ventola CL. Current Issues Regarding Complementary and
Alternative Medicine (CAM) in the United States. Part 1:
The widespread use of CAM and the need for
better-informed health care professionals to provide
patient counseling. PT 2010;35:461–8.
40. Bauer I, Guerra JJ. Physicians’ knowledge and
communication about traditional, complementary and
alternative medicine use among Latino patients at
Kaiser Permanente, Oakland CA. Field Actions Sci Rep
2014;8.
41. Hilal M, Hilal S. Knowledge, attitude, and utilization of
herbal medicines by physicians in the Kingdom of Bahrain:
a cross-sectional study. J Assn Arab Univ Basic Appl Sci
2017;24:325–33.
42. Lee RT, Barbo A, Lopez G, Melhem-Bertrandt A, Lin H,
Olopade OI, et al. National survey of US oncologists’
knowledge, attitudes, and practice patterns regarding herb
and supplement use by patients with cancer. J Clin Oncol
2014;32:4095–101.
43. Reddy KR, Belle SH, Fried MW, Afdha N, Navarro VJ, Hawke
RL, et al. Rationale, challenges, and participants in a Phase
II trial of a botanical product for chronic hepatitis C. Clin
Trials 2012;9:102–12.
44. Thatte UM. Clinical research with ayurvedic medicines.
Pharma Times 2005;37:9–10.
45. Parveen A, Parveen B, Parveen R, Ahmad S. Challenges and
guidelines for clinical trial of herbal drugs. J Pharm Bioallied
Sci 2015;7:329–33.
46. Kaur R, Gupta V, Chirstopher AF, Bansal P. Scope and
bottlenecks in clinical trials of herbal drugs-present
scenario. J Pharm Res 2015;14:26–32.
47. Goldman P. Herbal medicines today and the roots of
modern pharmacology. Ann Int Med 2001;8:135.
48. Mutua DN, Juma KK, Munene M, Njagi ENJ. Safety, efficacy,
regulations and bioethics in herbal medicines research and
practice. J Clin Res Bioethics 2016;7:3.
49. Dhanaukar SA, Thatte UM. Current status of ayurveda in
phytomedicine. Phytomedicine 1997;4:359–68.
50. Bower H. Double standards exist in judging traditional and
alternative medicine. Br Med J 1998;316:1694.
51. Lu A. GP-TCM RA Clinical Studies Interest Group – A Draft
Plan for Action; GP-TCM RA Clinical Studies Interest Group.
N.A. Chugh et al
Available from: http://www.gp-tcm.org/work-packages/
wp6-functional-genomics-in-clinical-studies-of-chinese-
herbal-medicines/.
52. Moreira DL, Teixeira SS, Monteiro MHD, De-Oliveira ACAX,
Paumgartten FJR. Traditional use and safety of herbal
medicines. Rev Bras Farmacogn 2014;24:248–57.
53. Linde K, Jonas WB, Melchart D, Willich S. The
methodological quality of randomized controlled trials of
homeopathy, herbal medicines and acupuncture. Int J
Epidemiol 2001;30:526–31.
54. Srinivasan K. Spices as influencers of body metabolism: an
overview of three decades of research. Food Res Int
2005;38:77–86.
55. Claraco AE, Hanna SE, Fargas-Babjak A. Reporting of
clinical details in randomized controlled trials of
acupuncture for the treatment of migraine/headaches and
nausea/vomiting. J Altern Complement Med 2003:151–9.
56. Bian ZX, Li YP, Moher D, Dagenais S, Liu L, Wu TX, et al.
Improving the quality of randomized controlled trials in
Chinese herbal medicine, part I: clinical trial design and
methodology. J Chin Integr Med 2006;4:120–9.
57. Gagniera JJ, Boon H, Rochona P, Moherd D, Barnesg J,
Bombardier C. Recommendations for reporting randomized
controlled trials of herbal interventions: explanation and
elaboration. J Clin Epidemiol 2006;59:1134–49.
58. Linde K, Willich SN. How objective are systematic reviews?
Differences between reviews on complementary medicine.
J R Soc Med 2003;96:617–22.
59. Davidson E, Vlachojannis J, Chrubasik MS. Best available
evidence in Cochrane reviews on herbal medicine. Evid
Based Complement Alternat Med 2013:1–7.
60. Liu ZL, Xie LZ, Zhu J, Li GQ, Grant SJ, Liu JP. Herbal
medicines for fatty liver diseases. Cochrane Database Syst
Rev 2013;8:CD009059.
61. Linde K, Barret B, Wolkart K, Bauer R, Meclhart D.
Echinaceae for preventing and treating the common cold.
Cochrane Database Syst Rev 2006;25:CD000530.
62. Myiasaka LS, Atallah AN, Soares BG. Valerian for anxiety
disorders. Cochrane Database Syst Rev 2006;4:CD004515.
63. Myiasaka LS, Atallah AN, Soares BG. Passiflora for anxiety
disorder. Cochrane Database Syst Rev 2007;1:CD004518.
64. Dat AD, Poon F, Pham KBT, Doust J. Aloe vera for treating
acute and chronic wounds. Cochrane Database Syst Rev
2012;2:CD008762.
65. Leach MJ, Moore V. Black cohosh (Cimicifuga spp.) for
menopausal symptoms. Cochrane Database Syst Rev
2012;12:CD007244.
66. Pittler MH, Ernst E. Systematic review: hepatotoxic events
associated with herbal medicinal products. Ailment
Pharmacol Ther 2003;18:451–71.
67. Wider B, Pittler MH, Thompson-Coon J, Ernst E. Artichoke
leaf extract for treating hypercholesterolaemia. Cochrane
Database Syst Rev 2013;28:CD003335.
68. Wah CL, Hock SC, Yun TK. Current scientific status and
regulatory control of traditional/herbal medicinal products:
globalisation challenges. Pharm Eng 2012;32.
69. Qi GD, We DA, Chung LP, Fai CK. Placebos used in clinical
trials for Chinese herbal medicine. Recent Pat Inflamm
Allergy Drug Discov 2008;2:123–7.
70. Willcox M, Benoit-Vical F, Fowler D, Bourdy G, Burford G,
Giani S, et al. Do ethnobotanical and laboratory data
predict clinical safety and efficacy of anti-malarial plants?
Malaria J 2011;10:S7.
71. Willcox M, Siegfried N, Johnson Q. Capacity for clinical
research on herbal medicines in Africa. J Altern Complement
Med 2012;18:622–8.
72. Herper M. The cost of creating a new drug now $5 billion,
pushing Big Pharma to change; 2013. Available from:
121
http://www.forbes.com/sites/matthewherper/2013/08/11/
how-the-staggering-cost-of-inventing-new-drugs-is-
shaping-the-future-of-medicine/.
73. Waynegarden W. The economics of pharmaceutical pricing;
2014. Available from: https://www.pacificresearch.org/
fileadmin/documents/Studies/PDFs/2013-2015/
PhamaPricingF.pdf.
74. Derendorf H. Pharmacokinetics of natural compounds.
Planta Med 2012;78:IL41,
http://dx.doi.org/10.1055/s-0032-320228.
75. Lee RT, Barbo A, Lopez G, Melhem-Bertrandt A, Lin H,
Olopade OI, et al. Curlin National survey of US oncologists’
knowledge, attitudes, and practice patterns regarding herb
and supplement use by patients with cancer. J Clin Oncol
2014;32:4095–101.
76. Coates PM, Paul MC, Blackman, Blackman MR, Cragg GM,
Levine M, White JD, Moss J, Levine MA, editors. Encyclopedia
of dietary supplements. New York, NY: Marcel Dekker; 2010.
77. Scott EN, Gescher AJ, Steward WPK. Development of dietary
phytochemical chemopreventive agents: biomarkers and
choice of dose for early clinical trials. Cancer Prev Res
2009;2:525–30.
78. Bhattaram VA, Graefe U, Kohlert C, Veit M, Derendorf H.
Pharmacokinetics and bioavailability of herbal medicinal
products. Phytomedicine 2002;3:1–33.
79. Cho HJ, Yoon IS. Pharmacokinetic interactions of herbs
with cytochrome P450 and P-glycoprotein. Evid Based
Complement Alternat Med 2015:10. Article ID 736431.
80. Bailey DG, Dresser GK. Natural products and adverse drug
interactions. CMAJ 2004;170:1531–2.
81. Bailey DG, Spence JD, Munoz C, Arnold JMO. Interaction of
citrus juices with felodipine and nifedipine. Lancet
1991;337:268–9.
82. Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J.
Indinavir concentrations and St John’s wort. Lancet
2000;355:547–8 [published erratum appears in Lancet
2001;357:1210].
83. Ruschitzka F, Meier PJ, Turina M, Luscher TT, Noll G. Acute
heart transplant rejection due to St. John’s wort. Lancet
2000;355:548–9.
84. Nicholas ET, Dzobo K, Chopera D, Wonkam A, Skelton M,
Blackhurst D, et al. Pharmacogenomics implications of
using herbal medicinal plants on African populations in
health transition. Pharmaceuticals (Basel) 2015;8:637–63.
85. Sharma AK, Kumar R, Mishra A, Gupta R. Problems
associated with clinical trials of Ayurvedic medicines. Braz J
Pharmacogn 2010;20:276–81.
86. Kunle OF, Egharevba HO, Ahmadu PO. Standardization of
herbal medicines – a review. Int J Biodivers Conserv
2012;4:101–12.
87. Dharmananda S. Dosage and forms of herbs: Decoctions,
Dried Decoctions, Powders, Pills, Etc. Available from:
http://www.itmonline.org/arts/dosage.htm.
88. Tomé-Carneiro J, Larrosa M, González-Sarrías A,
Tomás-Barberán F, García-Conesa MT, Espín JC. Resveratrol
and clinical trials: the crossroad from in vitro studies to
human evidence. Curr Pharm Des 2013;19:6064–93.
89. Xu Q, Feng Y, Duez P, Hendry BM, Hylands PJ. The hunt for
antifibrotic and profibrotic botanicals. Science
2014;346:S19–20.
90. Shetti S, Kumar CD, Sriwastava NK, Sharma IP.
Pharmacovigilance of herbal medicines: current state and
future directions. Pharmacogn Mag 2011;7:69–73.
91. Walj R, Boon H. Natural health product regulations:
perceptions and impact. Trends Food Sci Technol
2008;19:494–7.
92. Silano V, Coppens P, Larranaga-Guetaria A, Minghetti P,
Roth-Ehrang R. Regulations applicable to plant food
122
supplements and related products in the European Union.
Food Funct 2011;2:710–9.
93. Avigan MI, Mozersky RP, Seeff LB. Scientific and regulatory
perspectives in herbal and dietary supplement associated
hepatotoxicity in the United States. Int J Mol Sci 2016;17:331.
94. FDA. FDA regulation of drugs vs dietary supplements; 2015.
Available from: http://www.cancer.org/treatment/
treatmentsandsideeffects/complementaryandalternative
medicine/dietarysupplements/dietary-supplements-fda-
regulations.
95. Bazzie KL, Witmer DR, Pinto B, Bush C, Clark J, Deffenbaugh
Jr J. National survey of dietary supplement policies in acute
care facilities. Am J Health Syst Pharm 2006;63:65–70.
96. Shaw D, Ladds G, Duez P, Williamson E, Chan K.
Pharmacovigilance of herbal medicine. J Ethnopharmacol
2012;140:513–8.
97. Vanherweghem JL, Depierreux M, Tielemans C,
Abramowicz D, Dratwa M, Jadoul M, et al. Rapidly
progressive interstitial renal fibrosis in young women:
association with slimming regimen including Chinese
herbs. Lancet 1993;34:387–91.
98. Vanhaelen M, Vanhaelen-Fastre R, But P, Vanherweghem JL.
Identification of aristolochic acid in Chinese herbs. Lancet
1994;343:174.
99. Debelle FD, Vanherweghem JL, Nortier JL. Aristolochic acid
nephropathy: a worldwide problem. Kidney Int
2008;74:158–69.
100. European Medicines Agency (EMA). Public statement on the
risks associated with the use of herbal products containing
aristolochia species; 2005. Available from:
http://www.ema.europa.eu/docs/en GB/document library/
Scientific guideline/2010/04/WC500089957.pdf.
101. Cheung TP, Xue C, Leung K, Chan K, Li CG. Aristolochic
acids detected in some raw Chinese medicinal herbs and
manufactured herbal products—a consequence of
inappropriate nomenclature and imprecise labelling? Clin
Toxicol (Phila) 2006;44:371–8.
102. Martena MJ, van der Wielen JC, van de Laak LF, Konings EJ,
de Groot HN, Rietjens IM. Enforcement of the ban on
aristolochic acids in Chinese traditional herbal
preparations on the Dutch market. Anal Bioanal Chem
2007;389:263–75.
103. Jordan SA, Cunningham DG, Marles RJ. Assessment of
herbal medicinal products: challenges, and opportunities
to increase the knowledge base for safety assessment.
Toxicol Appl Pharmacol 2010;243:198–216.
104. Medicines and Healthcare Products Regulatory Agency.
Prohibited or restricted herbal ingredients; 2011. Available from:
http://www.mhra.gov.uk/howweregulate/medicines/
herbal-medicinesregulation/
prohibitedrestrictedherbalingredients/index.htm.
105. Vohra S, Cvijovic K, Boon H, Foster BC, Jaeger W,
LeGatt D, et al. Study of Natural Health Product Adverse
Reactions (SONAR): active surveillance of adverse events
following concurrent natural health product and
prescription drug use in community pharmacies. PLoS ONE
2012;7:e45196.
106. Charrois TL, Hill RL, Vu D, Foster BC, Boon HS, Cramer K,
et al. Community identification of natural health product
drug interactions. Ann Pharmacother 2007;41:1124–9.
107. Winslow LC, Shapiro H. Physicians want education about
complementary and alternative medicine to enhance
communication with their patients. Arch Intern Med
2002;162:1176–81.
108. Barnes J, Mills SY, Abbot NC, Willoughby M, Ernst E.
Different standards for reporting ADRs to herbal medicines
and conventional OTC medicines: face-to-face interviews
Integr Med Res ( 2 0 1 8 ) 109–125
with 515 users of herbal medicines. Br J Clin Pharmacol
1998;45:496–500.
109. van Grootheest K, Olsson S, Couper M, de Jong-van den
Berg L. Pharmacists’ role in reporting adverse drug
reactions in an international perspective.
Pharmacoepidemiol Drug Saf 2004;13:457–64.
110. Vickers KA, Jolly KB, Greenfield SM. Herbal medicine:
women’s views, knowledge and interaction with doctors: a
qualitative study. BMC Complement Altern Med 2006;6:1–8.
111. Tiralongo E, Braun L, Wilkinson JM, Spizer O, Bailey M,
Poole S, et al. Exploring the integration of complementary
medicines into Australian pharmacy practice with a focus
on different practice settings and background knowledge. J
Complement Integr Med 2010;7:1–21.
112. Coulter DM. PEM in New Zealand. In: Mann RD, Andrews EB,
editors. Pharmacovigilance. Chichester: Wiley; 2002:345–62.
113. Shakir SAW. PEM in the UK. In: Mann RD, Andrews EB,
editors. Pharmacovigilance. Chichester: Wiley; 2002:
333–44.
114. ICHs Steering Committee. ICH harmonized tripartite guideline,
pharmacovigilance planning; 2004. Available from:
www.ich.org/fileadmin/Public Web Site/ICH Products/
Guidelines/Efficacy/E2E/Step4/E2E Guideline.pdf.
115. McLernon DJ, Bond CM, Hannaford PC, Watson AJ, Lee L,
Avery HA. Adverse drug reaction reporting in the UK. Drug
Saf 2010;33:775–86.
116. Garret RG. Natural sources of metals in the environment.
Proc Int Symp Metal Ions Biol Med 2000;6:508–10.
117. Street RA. Heavy metals in medicinal plant products—an
African perspective. S Afr J Bot 2012;82:67–74.
118. Bauer R, Tittel G. Quality assessment of herbal preparations
as a precondition of pharmacological and clinical studies.
Phytomedicine 1996;2:193–8.
119. McLaren J, Swift W, Dillon P, Allsop S. Cannabis potency
and contamination: a review of the literature. Addiction
2008;103:1100–9.
120. Ulbricht C, Chao W, Costa D, Nguyen Y, Seamon E, Weissner
W. An evidence-based systematic review of green-lipped
mussel (Perna canaliculus) by the Natural Standard Research
Collaboration. J Diet Suppl 2009;6:54–90.
121. Armbruester N, Bryan K, Costa D, Giese N, Gruenwald J,
Iovin R, et al. Cinnamon (Cinnamomum spp.). Natural
Standard Professional Monograph; 2012. Available from:
http://www.naturalstandard.com/databases/
herbssupplements/all/cassia.asp.
122. Wang GW, Hu WT, Huang BK, Qin LP. Illicium verum: a
review on its botany, traditional use, chemistry and
pharmacology. J Ethnopharmacol 2011;136:10–20.
123. Ernst E. Adulteration of Chinese herbal medicines with
synthetic drugs: a systematic review. J Intern Med
2002;252:107–13.
124. Ernst E. Cardiovascular adverse effects of herbal medicines:
a systematic review of the recent literature. Can J Cardiol
2003;19:818–27.
125. Lynch E, Braithwaite R. A review of the clinical and
toxicological aspects of ‘traditional’ (herbal) medicines
adulterated with heavy metals. Expert Opin Drug Saf
2005;4:769–78.
126. Pittler MH, Ernst E. Systematic review: hepatotoxic events
associated with herbal medicinal products. Ailment
Pharmacol Ther 2003;18:451–71.
127. Affum O, Shiloh DO, Adomako D. Monitoring of arsenic
levels in some ready-to-use anti-malaria herbal products
from drug sales outlets in the Madina area of Accra, Ghana.
Food Chem Toxicol 2013;56:131–5.
128. Cohen PA, Ernst E. Safety of herbal supplements: a guide
for cardiologists. Cardiovasc Ther 2010;28:246–53.
N.A. Chugh et al
129. Posadzki P, Watson E. Contamination and adulteration of
herbal medicinal products (HMPs): an overview of
systematic reviews. Eur J Clin Pharmacol 2013;69:295–307.
130. WHO. WHO guidelines for assessing quality of herbal medicines
with reference to contaminants and residues; 2007. Available
from: http://apps.who.int/medicinedocs/documents/
s14878e/s14878e.pdf.
131. Rao MM, Meena AK, Galib G. Detection of toxic heavy
metals and pesticide residue in herbal plants which are
commonly used in the herbal formulations. Environ Monit
Assess 2011;181:267–71.
132. Prakash O, Jyoti KA, Kumar P, Manna NK. Adulteration and
substitution in Indian medicinal plants: an overview. J Med
Plants Stud 2013;1:127–32.
133. Ahmed S, Hasan MM. Crude drug adulteration: a concise
review. World J Pharm Sci 2015;4:274–83.
134. Cheng W, Ko W, Fan SG, Song L, Bian ZX. Evidence-based
management of herb–drug interaction in cancer
chemotherapy. Explore 2010;6:324–9.
135. Callaway E. Screen uncovers hidden ingredients of Chinese
medicine; 2012. Available from: http://www.nature.com/
news/screen-uncovers-hidden-ingredients-of-chinese-
medicine-1.10430.
136. Newmaster SG, Grguric M, Shanmughanandhan D,
Ramalingam S, Ragupathy S. DNA barcoding detects
contamination and substitution in North American herbal
products. BMC Med 2013;11:2–13.
137. Booker A. Up to 40% of some herbal supplements are
mislabelled or contain adulterants; 2016. Available from:
http://theconversation.com/up-to-40-of-some-herbal-
supplements-are-mislabelled-or-contain-adulterants-63859.
138. Shahid U. Herbal treatment strategies for breast cancer. In:
Malki AM, editor. Cancer treatment strategies. Foster City, CA,
USA: OMICS Group eBooks; 2014.
139. Rice T, Rosenau P, Unruh LY, Barnes AJ. Health systems in
transition. In: Saltman RB, van Ginneken E, eds. Health
system review. vol. 15. 2013.
140. Eskinazi D. Alternative medicine: definition, scope and
challenges. ABPN 2001;5:19–25.
141. Ernst E, Cohen MH, Stone J. Ethical problems arising in
evidence based complementary and alternative medicine.
Med Ethics 2004;30:156–9.
142. Joos S, Glassen K, Musselmann B. Herbal medicine in
primary healthcare in Germany: the patient’s perspective.
Evid Based Complement Alternat Med 2012;2012. Article ID
294638, 10 p.
143. Reynolds D. More Medicare, Medicaid patients turning to
alternative therapies?; 2010. Available from:
http://www.emaxhealth.com/1506/more-medicare-
medicaidpatients-turning-alternative-therapies.html.
144. National Center for Complementary and Alternative
Medicines (NCCAM). Paying for complementary and integrative
health approaches; 2011. Available from:
http://nccam.nih.gov/health/financial.
145. Shi L, Singh DA. Delivering health care in America: a systems
approach. 5th ed. Boston, MA: Jones & Bartlett; 2012.
146. Wiesener S, Falkenberg T, Hegyi G, Hök J, di Sarsina PR,
Fønnebø V. Legal status and regulation of CAM in Europe
Part I – CAM regulations in the European countries/Legal
status and regulation of complementary and alternative
medicine in Europe. Forsch Komplementmed 2012;19:
29–36.
147. Patwardhan B, Vaidya ADB, Chorghade M. Ayurveda and
natural products drug discovery. Curr Sci 2004;86:789–99.
148. Dasgupta T, Banerjee S, Yadava PK, Rao AR.
Chemopreventive potential of Azadirachta indica extract in
murine carcinogenesis model. J Ethnopharmacol
2004;92:23–36.
123
149. Koul A, Gangar SC, Sandhir R. Pitfalls in journey from
traditional to modern medicine. Nat Prod Rad 2005;4:6–14.
150. Gangar SC, Sandhir R, Rai DV, Koul A. Modulatory effects of
Azadirachta indica on benzo(a)pyrene induced forestomach
tumorigenesis in Balb/c mice. World J Gastroenterol
2006;12:2749–55.
151. Arora N, Koul A, Bansal MP. Chemopreventive activity of
Azadirachta indica on two-stage skin carcinogenesis in
murine model. Phytother Res 2011;25:408–16.
152. Bharati S, Rishi P, Koul A. Azadirachta indica exhibits
chemopreventive action against hepatic cancer: studies on
associated histopathological and ultrastructural changes.
Microsc Res Tech 2012;75:586–95.
153. Sharma C, Vas AJ, Goala P, Gheewala TM, Rizvi TA, Hussain
A. Ethanolic neem (Azadirachta indica) leaf extract prevents
growth of MCF-7 and HeLa cells and potentiates the
therapeutic index of cisplatin. J Oncol 2014:321754.
154. Arumugam A, Agullo P, Boopalan T, Nandy S, Lopez R,
Gutierrez C, et al. Neem leaf extract inhibits mammary
carcinogenesis by altering cell proliferation, apoptosis, and
angiogenesis. Cancer Biol Ther 2014;15:26–34.
155. Gupta P, Bansal MP, Koul A. Spectroscopic characterization
of lycopene extract from Lycopersicum esculentum (tomato)
and its evaluation as a chemopreventive agent against
experimental hepatocarcinogenesis in mice. Phytother Res
2013;27:448–56.
156. Koul A, Goyal R, Bharati S. Protective effect of Azadirachta
indica against Doxorubicin-induced cardiac toxicity in
tumour bearing mice. Indian J Exp Biol 2014;52:323–31.
157. Koul A, Shubhrant, Gupta P. Phytomodulatory potential of
lycopene from Lycopersicum esculentum against doxorubicin
induced nephrotoxicity. Indian J Exp Biol 2013;51:635–45.
158. Bala S, Chugh NA, Bansal SC, Garg ML, Koul A. Protective
role of Aloe vera against X-ray induced testicular
dysfunction. Andrologia 2017;49:e12697.
http://dx.doi.org/10.1111/and.12697.
159. Gehlot P, Soyal D, Goyal PK. Alterations in oxidative stress
in testes of Swiss albino mice by Aloe vera leaf extract after
gamma irradiation. Pharmacology online 2007:359–70.
160. Kumar A, Kumar R, Rahman MS, Iqubal MA, Anand G, Niraj
PK, et al. Phytoremedial effect of Withania somnifera against
arsenic-induced testicular toxicity in Charles Foster rats.
Avicenna J Phytomed 2015;5:355–64.
161. Li W, Zhang C, Du H, Huang V, Sun B, Harris JP, et al.
suppresses the up-regulation of acetyl-coA carboxylase 1
and skin tumor formation in a skin carcinogenesis mouse
model. Mol Carcinog 2016;55:1739–46.
162. Palliyaguru DL, Singh SV, Kensler TW. Withania somnifera:
from prevention to treatment of cancer. Mol Nutr Food Res
2016;60:1342–53.
163. Sarbishegi M, Khani M, Salimi S, Valizadeh M, Sargolzaei
AF. Antiproliferative and antioxidant effects of Withania
coagulans extract on benign prostatic hyperplasia in rats.
Nephrourol Mon 2016;8:33180.
164. Turrini E, Calcabrini C, Sestili P, Catanzaro E, Gianni E, Diaz
AR, et al. Withania somnifera induces cytotoxic and
cytostatic effects on human T leukemia cells. Toxins (Basel)
2016.
165. Tulsulkar J, Glueck B, Hinds TD, Shah ZA. Ginkgo biloba
extract prevents female mice from ischemic brain damage
and the mechanism is independent of the HO1/Wnt
pathway. Transl Stroke Res 2016;7:120–31.
166. Kaur S, Chhabra R, Nehru B. Ginkgo biloba extract
attenuates hippocampal neuronal loss and cognitive
dysfunction resulting from trimethyltin in mice.
Phytomedicine 2013;20:178–86.
167. Ribeiro ML, Moreira LM, Arçari DP, Dos Santos LF, Marques
AC, Pedrazzoli J, et al. Protective effects of chronic
124
treatment with a standardized extract of Ginkgo biloba
L. in the prefrontal cortex and dorsal hippocampus
of middle-aged rats. Behav Brain Res 2016;313:
144–50.
168. Zamberlam CR, Vendrasco NC, Oliveira DR, Gaiardo RB,
Cerutti SM. Effects of standardized Ginkgo biloba extract on
the acquisition, retrieval and extinction of conditioned
suppression: Evidence that short-term memory and
long-term memory are differentially modulated. Physiol
Behav 2016;165:55–68.
169. Chandra S, Sah K, Bagewadi A, Keluskar V, Shetty A,
Ammanagi R, et al. Additive and synergistic effect of
phytochemicals in prevention of oral cancer. Eur J Gen Dent
2012;1:142–7.
170. Miller PE, Snyder DC. Phytochemicals and cancer risk: a
review of the epidemiological evidence. Nutr Clin Pract
2012;27:599–612.
171. Fedder MD, Jakobsen HB, Giversen I, Christensen LP, Parner
ET, Fedder J. An extract of pomegranate fruit and galangal
rhizome increases the numbers of motile sperm: a
prospective, randomised, controlled, double-blinded trial.
PLOS ONE 2014;9:e108532.
172. Bar Sela G, Wollner M, Hammer L, Agbarya A, Dudnik E,
Haim N. Mistletoe as complementary treatment in patients
with advanced non-small-cell lung cancer treated with
carboplatin-based combinations: a randomised phase II
study. Eur J Cancer 2013;49:58–64.
173. Büechi S, Vögelin R, von Eiff MM, Ramos M, Melzer J. Open
trial to assess aspects of safety and efficacy of a combined
herbal cough syrup with ivy and thyme. Forsch
Komplementarmed Klass Naturheilkd 2005;12:328–32.
174. Latil A, Pétrissans MT, Rouquet J, Robert G, de la Taille A.
®
Effects of hexanic extract of Serenoa repens (Permixon
160 mg) on inflammation biomarkers in the treatment of
lower urinary tract symptoms related to benign prostatic
hyperplasia. Prostate 2015;75:1857–67.
175. Shukla S, Bharti AC, Hussain S, Mahata S, Hedau S, Kailash
U, et al. Elimination of high-risk human papillomavirus
type HPV16 infection by ‘Praneem’ polyherbal tablet in
women with early cervical intraepithelial lesions. J Cancer
Res Clin Oncol 2009;135:1701–9.
176. Stebbings S. Trial to investigate the efficacy and safety of
an extract of Artemisia annua administered over 12 weeks,
for managing pain, stiffness, and functional limitation
associated with osteoarthritis of the hip and knee. Clin
Rheumatol 2016;35:1829–36.
177. Mosihuzzaman M, Choudhary MI. Protocols on safety,
efficacy, standardization, and documentation of herbal
medicine (IUPAC technical report). Pure Appl Chem
2008;80:2195–230.
178. European Medicines Agency (EMA). Herbal medicinal
products. Available from: http://www.ema.
europa.eu/ema/index.jsp?curl=pages/regulation/general/
general content 000208.jsp.
179. European Food Safety Authority (EFSA) guidance on safety
assessment of botanicals and botanical preparations
intended for use as ingredients in food supplements. Eur
Food Saf Auth J 2009;7:1249.
180. Kew Royal Botanic Gardens. Medicinal plants names
services. Available from: http://www.kew.org/kew-
science/people-and-data/resources-and-databases/
medicinal-plant-names-services.
181. UMC. 2011. Available at:
http://www.who-umc.org/graphics/24727.pdf.
182. Strandell J, Caster O, Bate A, Norén GN, Edwards IR.
Reporting patterns indicative of adverse drug interactions:
a systematic evaluation in VigiBase. Drug Saf
2011;34:253–66.
Integr Med Res ( 2 0 1 8 ) 109–125
183. Association of South East Asian Nations. Harmonization of
standards and technical requirements in ASEAN. Available
from: http://www.asean.org/18215.htm.
184. Association of South East Asian Nations (ASEAN). Profile of
definition, terminology and technical requirement of
traditional medicines and health supplements among
ASEAN member states. Available from:
http://www.asean.org/20258.pdf.
185. Kartal M. Intellectual property protection in the natural
product drug discovery, traditional herbal medicine and
herbal medicinal products. Phytotherapy Res 2007;21:113–9.
186. Musthaba M, Baboota S, Athar TMD, Thajudeen KY, Ahmed
S, Ali J. Patented herbal formulations and their therapeutic
applications. Recent Pat Drug Deliv Formul 2010;4:231–44.
187. Wang X, Chan AW. Challenges and patenting strategies for
Chinese herbal medicines. Chin Med 2010;5:24.
188. Sahoo N, Manchikanti P, Dey SH. Herbal drug patenting in
India: IP potential. J Ethnophramacol 2011;137:289–97.
189. Gagnier JJ, Boon H, Rochon P, Moher D, Barnes J, Bombardier
C, CONSORT Group. Reporting randomized controlled trials
of herbal interventions: an elaborated CONSORT
statement. Ann Intern Med 2006;144:364–7.
190. Schulz KF, Altman DG, Moher D. CONSORT 2010 Statement:
updated guidelines for reporting parallel group randomized
trials. Int J Surg 2011;9:672–7.
191. Wu T, Harrison RA, Chen X, Ni J, Zhou L, Qiao J, et al.
Tongxinluo capsule for unstable angina pectoris. Cochrane
Database Syst Rev 2006;4:CD004474.
192. Wolsko PM, Solondz DK, Phillips RS, Schachter SC,
Eisenberg DM. Lack of herbal supplement characterization
in published randomized controlled trials. Am J Med
2005;118:1087–93.
193. Zhang JL, Cui M, He Y, Yu HL, Guo DA. Chemical fingerprint
and metabolic fingerprint analysis of Danshen Injection by
HPLC-UV and HPLC-MS methods. J Pharm Biomed Anal
2005;36:1029–35.
194. Linde K, Jonas WB. Evaluating complementary and
alternative medicine: the balance of rigor and relevance. In:
Jonas WB, Levin JS, editors. Essentials of complementary and
alternative medicine. Baltimore: Lippincott Williams &
Wilkins; 1999:57–71.
195. Turner RB, Bauer R, Woelkart K, Hulsey TC, Gangemi JD. An
evaluation of Echinacea angustifolia in experimental
rhinovirus infections. N Engl J Med 2005;353:341–8.
196. Gupta P. Pharmacogenetics, pharmacogenomics and
ayurgenomics for personalized medicine: a paradigm shift.
Indian J Pharm Sci 2015;77:135e141.
197. Jaiswal YS, Williams LL. A glimpse of Ayurveda: the
forgotten history and principles of Indian traditional
medicine. J Tradit Complement Med 2017;7:50–3.
198. European Medicines Agency. Reflection paper on marker used
for quantitative and qualitative analysis of herbal medicinal
products and traditional herbal medicinal products; 2008.
Available from: http://www.ema.europa.eu/docs/en
GB/document library/Scientific guideline/2009/09/
WC500003211.pdf.
199. Tistaert C, Dejaegher B, Heyden YV. Chromatographic
separation techniques and data handling methods for
herbal fingerprints: a review. Anal Chim Acta
2011;690:148–61.
200. Zeng Z, Chau FT, Chan HY, Cheung CY, Lau TY, Wei S, et al.
Recent advances in the compound oriented and pattern
oriented approaches to the quality control of herbal
medicine. Chin Med 2008;3:9.
201. Xie PS, Leung AY. Understanding the traditional aspect of
Chinese medicine in order to achieve meaningful quality
control of Chinese materia medica. J Chromatogr A
2009;1216:1933–40.
N.A. Chugh et al
202. Crockett SL, Khan IA. Challenges of standardization:
marker compounds in plant species related and
unrelated to top selling herbs. J Herbs Spices Med Plants
2003;10:13–24.
203. Xie P, Chen S, Liang YZ, Wang X, Tian R, Upton R.
Chromatographic fingerprint analysis—a rational approach
for quality assessment of traditional Chinese herbal
medicine. J Chromatogr A 2006;1112:171–80.
204. Fan XH, Cheng YY, Ye ZL, Lin RC, Qian ZZ. Multiple
chromatographic fingerprinting and its application to the
quality control of herbal medicines. Anal Chim Acta
2006;555:217–24.
205. Jiang Y, David B, Tu P, Barbin Y. Recent analytical
approaches in quality control of traditional Chinese
medicines—a review. Anal Chim Acta 2010;657:9–18.
206. Ciesla L, Bogucka-Kocka A, Hajnos M, Petruczynik A,
Waksmundzka-Hajnos M. Two dimensional thin layer
chromatography with adsorbent gradient as a method of
chromatographic fingerprinting of furanocoumarins for
distinguishing selected varieties and forms of Heracleum
spp. J Chromatogr 2008;1207:160–8.
207. Ciesla L, Waksmundzka-Hajnos M. Two dimensional thin
layer chromatography in the analysis of secondary plant
metabolites. J Chromatogr A 2009;1216:1035–52.
208. Holmes E, Tang H, Wang Y, Seger C. The assessment of
plant metabolite profiles by NMR-based methodologies.
Planta Med 2006;72:771–85.
209. Krishnan P, Kruger NJ, Ratcliffe RG. Metabolite
fingerprinting and profiling in plants using NMR. J Exp Bot
2005;56:255–65.
210. Kim HK, Choi YH, Erkelens C, Lefeber AW, Verpoorte R.
Metabolic fingerprinting of Ephedra species using 1H-NMR
spectroscopy and principal component analysis. Chem
Pharm Bull 2005;53:105–9.
211. Venhuis BJ, Tan J, Vredenbergt MJ, Ge X, Low MY, de Kaste
D. Capsule shells adulterated with Tadalafil. Forensic Sci Int
2012;214:20–2.
212. Health Sciences Authority. HAS warns against consuming “XP
Tongkat Ali Supreme” capsules found to contain undeclared
potent substances; 2009. Available from: http://www.hsa.gov.
sg/content/hsa/en/News Events/Press Releases/2009/hsa
warns against0.html.
213. Yuen YP, Lai CK, Poon WT, Ng SW, Chan AY, Mak TW.
Adulteration of over-the counter slimming products with
pharmaceutical analogues—an emerging threat. Hong Kong
Med J 2007;13:216–20.
125
214. Singh S, Prasad B, Savaliya AA. Strategies for characterizing
sildenafil, vardenafil, tadalafil and their analogues in herbal
dietary supplements, and detecting counterfeit products
containing these drugs. Trends Anal Chem 2009;28:13–28.
215. Vaysse J, Gilard V, Balayssac S, Zedde C, Martino R,
Malet-Martino M. Identification of a novel sildenafil
analogue in an adulterated herbal supplement. J Pharm
Biomed 2012;59:58–66.
216. Lee HM, Kim CS, Jang YM, Kwon SW, Lee BJ. Separation and
structural elucidation of a novel analogue of vardenafil
included as an adulterant in a dietary supplement by liquid
chromatography-electrospray ionization mass
spectrometry, infra red spectroscopy and nuclear magnetic
resonance spectroscopy. J Pharm Biomed 2011;54:491–6.
217. Chawla R, Thakur P, Chowdhry A, Jaiswal S, Sharma A, Goel
R, et al. Evidence based herbal drug standardization
approach in coping with challenges of holistic
management of diabetes: a dreadful lifestyle disorder of
21st century. J Diabetes Metab Disord 2013;12:35.
218. Diabetes action now—an initiative of the World Health
Organisation and International Diabetes Federation; 2004:20.
219. Silva Juìnior JOC, Costa RMR, Teixeira FM, Barbosa WLR.
Processing and quality control of herbal drugs and their
derivatives. In: Shoyama Y, editor. Quality control of herbal
medicines and related areas. 2011:195–222.
220. Yongyu Z, Shujun S, Jianye D, Wenyu W, Huijuan C, Jianbing
W. Quality control method for herbal medicine. Chem
Fingerprint Anal 2011;16:171–94.
221. Singh SK, Chaudhary A, Rai DK, Rai SK. Preparation and
characterization of a mercury based Indian traditional drug
– Rassindoot. Int J Tradit Knowl 2009;8:346–51.
222. Svicekova M, Havranek E, Novak V. Determination of heavy
metals in samples of herbal drugs using differential pulse
polarography. J Pharm Biol 1993;42:68–70.
223. Ip SP, Zhao M, Xian Y, Chen M, Zong Y, Tjong YW. Quality
assurance for Chinese herbal formulae: standardization of
IBS-20, a 20-herb preparation. J Chin Med 2010;5:1–10.
224. Shen AQ, Morgan L, Barroso ML, Zhang X. Tandem method
development of LC–MS analysis of aminoglycoside drugs:
challenges and solutions. Answ Pharm Questions Discip
Ingenuity 2010;5:567–9.
225. Di X, Kelvin KCC, Leung HW, Carmen WH. Fingerprint
profiling of acid hydrolyzates of polysaccharides extracted
from the fruiting bodies and spores of Lingzhi by
high-performance thin-layer chromatography. J Chromatogr
A 2003;1018:85–95.